WO2011071239A2 - Procédé de solubilisation d'une matière active difficilement soluble/insoluble par la formation de composite d'oligomères - Google Patents

Procédé de solubilisation d'une matière active difficilement soluble/insoluble par la formation de composite d'oligomères Download PDF

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WO2011071239A2
WO2011071239A2 PCT/KR2010/007066 KR2010007066W WO2011071239A2 WO 2011071239 A2 WO2011071239 A2 WO 2011071239A2 KR 2010007066 W KR2010007066 W KR 2010007066W WO 2011071239 A2 WO2011071239 A2 WO 2011071239A2
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insoluble
oligomer
formation
acid
oligomeric complex
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PCT/KR2010/007066
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Korean (ko)
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WO2011071239A3 (fr
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김철환
고승학
심재성
권은경
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(주)바이오제닉스
최용환
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Priority to EP10836135.3A priority Critical patent/EP2511345B1/fr
Priority to JP2012536653A priority patent/JP5629327B2/ja
Priority to US13/505,011 priority patent/US9139703B2/en
Publication of WO2011071239A2 publication Critical patent/WO2011071239A2/fr
Publication of WO2011071239A3 publication Critical patent/WO2011071239A3/fr

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    • C08J3/00—Processes of treating or compounding macromolecular substances
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    • C08L93/00—Compositions of natural resins; Compositions of derivatives thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
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    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
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    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
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    • C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
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    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
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    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/12—Agar or agar-agar, i.e. mixture of agarose and agaropectin; Derivatives thereof
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    • C08L61/00—Compositions of condensation polymers of aldehydes or ketones; Compositions of derivatives of such polymers
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    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention forms a structure having a hydrophobic pore structure by using oligomers derived from two hydrophilic natural polymers and encapsulates the egg / insoluble component in the pupil structure, thereby self-aggregation of the egg / insoluble material.
  • the present invention relates to a solubilization method of an insoluble / insoluble active substance through the formation of an oligomeric complex which effectively solubilizes by increasing thermodynamic stability while suppressing the antimicrobial activity.
  • Solubilization is a process of enhancing the solubility by any manipulation of a substance that is insoluble in water or aqueous solution.
  • Traditional techniques for improving solubility and increasing drug absorption include the use of organic solvents such as ethanol or surfactants as additives, the preparation of salts in the presence of ionizing groups, and the adjustment of pH to adjust solubility. How to increase.
  • the problem of the present invention is to form a structure having a hydrophobic pore structure by using oligomers derived from two hydrophilic natural polymers and to encapsulate the egg / insoluble component in the pore structure, thereby self-aggregating the self / insoluble material (self).
  • the present invention relates to a solubilization method of an insoluble / insoluble active substance through formation of an oligomeric complex that effectively solubilizes by increasing thermodynamic stability while inhibiting -aggregation.
  • the solubilization method of the insoluble / insoluble active material through the formation of the oligomeric complex of the present invention comprises the steps of preparing oligomeric complexes having a pupil structure by mixing oligomers derived from two hydrophilic natural polymers and dissolving them in water; It is characterized in that it comprises a second step of encapsulating it in the hydrophobic pupil structure of the oligomer complex by adding an egg / insoluble material to the oligomer complex.
  • the step of filtering or centrifuging the reaction solution to remove the remaining egg / insoluble material not encapsulated in the oligomer complex further comprises a four steps of removing and drying the water and the organic solvent (if used) in the reaction solution from which the residue is removed.
  • an oligomer structure having a hydrophobic pore structure is formed by physical bonding between molecules, and thus the egg / insoluble material is encapsulated in an egg / water solution in an aqueous solution.
  • the oligomeric complex in which the egg / insoluble substance is encapsulated prevents precipitation due to reaggregation of the egg / insoluble substances, and thus has excellent dissolution stability, and does not involve a chemical reaction, thereby maintaining the intrinsic physiological activity of the egg / insoluble substance. It can be maintained.
  • the oligomeric complex in which the poorly insoluble substance is encapsulated has an advantage of improving water solubility, dissolution stability, and the like of the active material.
  • the oligomeric composites containing the insoluble / insoluble components prepared through this have excellent dissolution stability and can be applied as functional raw materials of the cosmetic industry, and other industries (food, pharmaceuticals, etc.) that require solubilization of insoluble / insoluble materials. You can also extend the applicability.
  • FIG. 1 is a view showing a structure in which an egg / insoluble material is enclosed in the pupil structure of the oligomeric composite of the present invention.
  • the basic concept of the present invention is to prevent the aggregation and re-aggregation of the egg / insoluble components to prevent precipitation and dissolution in the aqueous solution when the egg / insoluble materials are encapsulated in the oligomer complex having a hydrophobic pupil structure Enhancement of the stability does not involve chemical reactions that can alter the structure of the insoluble / insoluble components, and encapsulates these components in a physically formed pore-structured oligomer structure to maintain the original physiological activity.
  • the method for preparing the oligomer complex of the present invention comprises the steps of preparing an oligomer complex having a physical pupil structure by mixing oligomers derived from two kinds of hydrophilic natural polymers and dissolving in water; And adding an egg / insoluble material to the oligomer complex and encapsulating it in the hydrophobic pupil structure of the oligomer complex.
  • Natural polymer oligomers are selected from xanthan gum, acacia gum, guar gum, gum arabic, agar, alginic acid, chitosan, pectin, carboxyalkylcellulose, maltodextrin, dextrin and hyaluronic acid.
  • Two selected natural polymer oligomers were used in a ratio of 1: 1 to 1:10 by weight in distilled water, and in particular, 1: 2 to 1: 4 by weight.
  • the weight ratio of one type of natural polymer oligomer is too high among the two types of natural polymer oligomers, the hydrophobic pore structure of the oligomer composite is not properly formed, and the encapsulation effect of the insoluble / insoluble active ingredient is lowered.
  • the weight ratio of the two kinds of natural polymer oligomer and water is used from 1: 1 to 1: 100 weight ratio.
  • the weight ratio of the natural polymer oligomer to water is too high, the viscosity of the solution is excessively increased by the natural polymer oligomers, making it difficult to prepare the oligomeric composite solution, on the contrary, when the weight ratio of the natural polymer oligomer to water is too low, Since the intermolecular physical bonding strength of the heavy oligomer complex is relatively reduced, the hydrophobic pore structure is not formed properly, and thus the encapsulation effect of the egg / insoluble active ingredient is lowered.
  • the average molecular weight of the natural polymer oligomer is preferably 1,000 to 100,000.
  • the preparation temperature at the time of preparing the oligomer composite may be at 20 ⁇ 80 °C, in particular, it is preferable to manufacture at 40 ⁇ 50 °C.
  • the pH of the solution is preferably maintained at 5-8.
  • the second step of adding the egg / insoluble material and encapsulating it in the hydrophobic pore structure of the oligomer complex it was added by simple addition or by dissolving in an organic solvent.
  • an egg / insoluble substance is gradually added at 0.1 to 99% by weight based on the total weight of solids. At this time, it is preferable to add in 1 to 20% by weight.
  • the egg / insoluble component exceeds 99% by weight, it is beyond the limiting capacity of the hydrophobic pupil structure in the oligomer composite that can encapsulate the egg / insoluble component, so that the effect of improving the solubility of the egg / insoluble component is lowered.
  • the insoluble / insoluble material in the second step is 20 ⁇ 80 °C is suitable, preferably stirred at a temperature of 40 ⁇ 50 °C.
  • pH 5-8 is suitable, Preferably it is good to maintain pH6.5-7.5. If the temperature and pH are not controlled, there is a disadvantage in that the egg / insoluble active component is not properly encapsulated in the oligomer composite due to the collapse of the hydrophobic pupil structure due to the degradation of the physical bond between the natural polymer oligomers forming the oligomer complex.
  • the organic solvent may also be selected from methanol, ethanol, acetone, tetrahydrofuran (THF), acetonitrile (AN).
  • the egg / insoluble materials include amentoflavone, ellagic acid, apigenin, verginin, berginin, diosmetin, univestin, resveratrol, Polyphenols such as isoflavones and catechins, salicylic acid, alpha lipoic acid, caffeine, tocopherol, docosahexaenoic acid (DHA-Docosahexaenoic acid) ), Oily fatty acids such as eicosapentaenoic acid (EPA), conjugated linolenic acid (CLA), ginkgo leaf extract, red ginseng extract, and natural extracts containing polyphenols. .
  • EPA eicosapentaenoic acid
  • CLA conjugated linolenic acid
  • ginkgo leaf extract ginkgo leaf extract
  • red ginseng extract and natural extracts containing polyphenols.
  • step 2 the reaction solution is filtered or centrifuged to remove residual egg / insoluble material not encapsulated in the oligomer complex, and water and organic solvent (if used) are removed from the reaction solution from which the residue is removed. It further comprises four steps of drying.
  • dissolution stability may be improved by introducing the insoluble materials into the oligomeric complex having a pore structure to increase the solubility of the insoluble components in the aqueous solution.
  • the physical density and physical bond strength is increased to physically improve the material having insoluble / insoluble characteristics Encapsulation was improved by phosphorus bonding to improve solubility.
  • the formed oligomer aqueous solution is maintained at 40-50 [deg.] C., pH 6.5-7.5, and a certain amount is gradually added to the oligomer aqueous solution using ellagic acid as a representative material of the insoluble / insoluble substance.
  • ellagic acid as a representative material of the insoluble / insoluble substance.
  • elilic acid is added, it is mixed and stirred at a temperature of 40 to 50 ° C.
  • the pH was maintained at 6.5 ⁇ 7.5 so that the ellagic acid is completely mixed in the oligomer aqueous solution.
  • the prepared aqueous solution was centrifuged or filtered to measure the amount of precipitate, and the filtrate was powdered using a lyophilizer to prepare a control.
  • ellagic acid was added to the solution in which the natural polymer oligomer was dissolved, mixed, and the precipitate was dried during centrifugation to measure the weight of the insoluble precipitate.
  • the prepared control powder was quantified and placed in distilled water to make 100 ml, and stirred for 30 minutes to prepare an aqueous solution.
  • the prepared aqueous solution was put into a centrifuge tube weighed in advance and centrifuged. The supernatant was poured out, and the tube was dried in a vacuum dryer at 60 ° C. for 5 days, and then the weight change was measured to measure the amount of precipitate. The solubility in water of the oligomeric complex containing the insoluble material was calculated.
  • the supernatant centrifuged was stored for 4 weeks at 0 °C, 1 week, 2 weeks, 3 weeks, 4 weeks and observed whether the precipitate was visually.
  • the formed oligomeric complex solution is maintained at 40-50 ° C., pH6.5-7.5, and a certain amount is gradually added to the oligomeric complex solution using ellagic acid as a representative material of the insoluble / insoluble substance.
  • ellagic acid When ellagic acid is added, it mixes and stirs at the temperature of 40-50 degreeC. At this time, the pH was maintained at 6.5 ⁇ 7.5 to encapsulate the ellagic acid into the hydrophobic pore structure of the oligomer complex.
  • the reaction solution was centrifuged or filtered to measure the weight of ellagic acid removed without being encapsulated, and the supernatant or filtrate was powdered using a lyophilizer to prepare an oligomeric complex encapsulated with ellagic acid.
  • Dextrin and maltodextrin in natural polymer oligomer are put in distilled water at a constant ratio as shown in [Table 6] and maintained at 40 ⁇ 50 °C, and maintained at pH5 ⁇ 8 using pH adjuster. Stir until complete dissolution to form oligomeric complex.
  • the oligomeric complex solution formed was maintained at 40-50 ° C., pH6.5-7.5.
  • a small amount of the insoluble / insoluble substance was added to the organic solvent or dissolved in a concentration of 1 to 50%, and then slowly added to the oligomeric complex solution to encapsulate the hydrophobic pupil structure of the oligomeric complex.
  • the reaction solution was centrifuged or filtered to measure the weight of the insoluble / insoluble material removed.
  • Oligomeric composites containing insoluble / insoluble materials were prepared.
  • the egg / insoluble material was added to the solution in which the two kinds of natural polymer oligomer complexes were mixed, followed by mixing and drying the precipitate during centrifugation or filtration to insoluble precipitate. The weight of the was measured.
  • the oligomeric composite powder containing the egg / insoluble material prepared in Examples 1 to 138 was quantified and placed in distilled water to make 100 ml, and stirred for 30 minutes to prepare an aqueous solution.
  • the prepared aqueous solution was put into a centrifuge tube weighed in advance and centrifuged. The supernatant was poured out, and the tube was dried in a vacuum dryer at 60 ° C. for 5 days, and then the weight change was measured to measure the amount of precipitate.
  • the solubility in water of the oligomeric complex containing the insoluble material was calculated.
  • the supernatant centrifuged was stored for 4 weeks at 0 °C, 1 week, 2 weeks, 3 weeks, 4 weeks and observed whether the precipitate was visually.
  • the solubility of the egg / insoluble materials can be improved and solubility stability can be improved. Not only can be applied as a functional raw material of the cosmetic industry of / insoluble substances, but also can be extended to other industries (food, pharmaceuticals, etc.) that require solubilization of insoluble / insoluble substances.

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Abstract

La présente invention concerne un procédé de solubilisation d'une matière active difficilement soluble/insoluble par la formation d'un composite d'oligomères. Une structure ayant des cavités hydrophobes est formée à l'aide d'oligomères issus de deux sortes de polymères naturels hydrophiles, et un composant difficilement soluble/insoluble est chargé dans les cavités, permettant ainsi d'inhiber l'auto-agrégation d'une matière difficilement soluble/insoluble et d'augmenter la stabilité thermodynamique de façon à solubiliser de manière efficace la matière difficilement soluble/insoluble. La présente invention comprend premièrement le mélange d'oligomères issus de deux sortes de polymères naturels hydrophiles et de dissolution des oligomères mélangés dans l'eau pour préparer un composite d'oligomères ayant une structure à cavités ; et deuxièmement, l'addition d'une matière difficilement soluble/insoluble au composite d'oligomères pour charger la matière difficilement soluble/insoluble dans la structure à cavités hydrophobes du composite d'oligomères.
PCT/KR2010/007066 2009-12-09 2010-10-15 Procédé de solubilisation d'une matière active difficilement soluble/insoluble par la formation de composite d'oligomères WO2011071239A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP10836135.3A EP2511345B1 (fr) 2009-12-09 2010-10-15 Procédé de solubilisation d'une matière active difficilement soluble/insoluble par la formation de composite d'oligomères
JP2012536653A JP5629327B2 (ja) 2009-12-09 2010-10-15 オリゴマー複合体の形成による難溶性／不溶性活性物質の可溶化方法
US13/505,011 US9139703B2 (en) 2009-12-09 2010-10-15 Method of solubilizing poorly soluble/insoluble active material through formation of oligomer composite

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KR10-2009-0121886 2009-12-09
KR1020090121886A KR101138258B1 (ko) 2009-12-09 2009-12-09 올리고머 복합체의 형성을 통한 난/불용성 활성물질의 가용화 방법

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US20120219604A1 (en) 2012-08-30
EP2511345A4 (fr) 2014-07-23
KR101138258B1 (ko) 2012-04-24
WO2011071239A3 (fr) 2011-11-03
US9139703B2 (en) 2015-09-22
JP5629327B2 (ja) 2014-11-19
EP2511345A2 (fr) 2012-10-17
EP2511345B1 (fr) 2018-12-19
KR20110065055A (ko) 2011-06-15
JP2013509481A (ja) 2013-03-14

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